Tobacco use is a serious health problem in the United States: over 435,000 deaths each year are attributed to smoking, and although 42% of smokers attempt to quit each year, less than 6% are successful. These statistics suggest that current smoking cessation treatments are not adequate. One motivating factor that may contribute to both the maintenance of nicotine addiction and relapse is nicotine withdrawal effects. Withdrawal symptoms reported by smokers include insomnia, increased appetite, affective changes, and cognitive deficits. In fact, changes in cognition during abstinence predict relapse; suggesting that understanding the neural and genetic substrates underlying these changes could facilitate development of more efficacious treatments. Great advances have been made in understanding nicotine addiction but there are serious gaps in our knowledge of nicotine withdrawal. For instance, examination of the neurobiological substrates of nicotine withdrawal disruption of cognitive processes is limited and examination of genetic influences is nonexistent. A goal of this proposal is to identify the genetic and neurobiological substrates of nicotine withdrawal deficits in contextual conditioning, a cognitive process. This proposal will use traditional behavioral genetic techniques and genetically modified mice to achieve this goal. Characterizing the dynamics of nicotine withdrawal will further understanding of nicotine addiction and aid in understanding the relationship between the behavioral effects of nicotine and changes in receptor function and downstream processes. Identification of the genetic and neural substrates of nicotine withdrawal will aid development of new treatments for nicotine withdrawal symptoms and in the tailoring of treatments to produce the most effective results. In studies of smokers, it is clear that changes in cognitive processes during abstinence are an important component of nicotine withdrawal. One thing that is striking when examining the literature on animal models of withdrawal is the dearth of information on the genetic and neural substrates of nicotine withdrawal deficits in cognitive processes. This proposal will examine the pharmacology, the neurobiology, and the genetics of nicotine withdrawal disruption of contextual learning in mice. Identifying neurobiological and genetics factors that contribute to the effects of nicotine is important for understanding nicotine addiction and for developing novel treatments that could potentially be tailored by genotype to provide the most effective treatment.